The present invention relates to a method of obtaining acid soluble proteins of micellar casein, to fractions of the proteins, to the proteins for use as a medicament and to the use of the proteins in the manufacture of medicament or consumable products.
Diabetes mellitus is one of the most widespread diseases in the world. There are two major forms of diabetes mellitus: type I and type II. Type I diabetic patients are characterised by an autoimmune destruction of their insulin secreting pancreatic beta cells. Type II diabetic patients, which represent 90-95% of all diabetic patients, are characterized by development of insulin resistance in the peripheral tissues (principally liver and muscle), and an inappropriate insulin secretion capacity.
People with type II diabetes are at high risk for serious long-term complications. These are essentially cardiovascular diseases, but also retinopathies, nephropathies and neuropathies.
Actual treatments for type II diabetes comprise several classes of drugs, which can be used alone or in combination with insulin, depending on the amount of insulin still produced (sulfonylureas, thiazolidinediones, for example). Eventually, when no insulin is produced any more, drug treatments may be replaced by injection of insulin alone.
Insulin biosynthesis and proinsulin gene expression are stimulated by Glucagon-Like Peptide-1 (GLP-1), expressed almost exclusively in endocrine intestinal cells. The important role of this secretagogue hormone is well summarised in “Glucagone-like peptide-1: a major regulator of pancreatic b-cell function, R. Perfetti and P. Merkel, European Journal of Endocrinology (2000), 143, 717-725, which document is incorporated herein by way of reference.
It was shown, for example, that after administration of intravenous GLP-1, the insulin secretory response type II diabetics was restored to that of normal patients.
Furthermore, GLP-1 inhibits gastric motility, gastric acid secretion, gastric emptying and delays enzymatic breakdown and absorption of nutrients. These affects are mostly preserved in both, type I and II diabetic patients
Moreover, GLP-1 was demonstrated to have an effect on satiety and is likely to be involved in decreased food intake.
GLP-1 is thus considered to be an ideal candidate for the treatment of diabetes.
Moreover, whenever one molecule of GLP-1 is liberated, one molecule of Glucagon-Like Peptide-2 (GLP-2) is also liberated. Originating from one single mRNA, the mammalian proglucagon transcript. GLP-1 and GLP-2 are thus co-secreted in the gut.
GLP-2 inhibits gastric secretion and gastric motility. Chronic treatment with GLP-2 has beneficial trophic effects on the intestine, such as enhancing tissue mass and mucosal thickness, decreasing the rate of enterocyte apoptosis, just to mention a few. An overview on GLP-1 synthesis, secretion and biological activity may be derived from: Glucagon-Like Peptide 2, D. J. Drucker, The Journal of Clinical Endocrinology and Metabolism, 2001, 86, 1759-64.
In WO 01/37850 (Société des Produits Nestlé) for the first time an in vitro cell model to measure proglucagon gene expression and GLP-1 secretion is described. The cell-line is called NCI-H716 and is deposited, for example, under the ATCC number CCL-250. Accordingly, certain milk protein hydrolysates stimulate GLP-1 secretion.
WO 98/31239 describes a method for the selective hydrolysis of casein in the presence of at least one further protein constituent. It is mentioned that the preparations so obtained are beneficial with respect to diabetes.
The objective of the present invention is one or several molecules that stimulate the secretion of proglucagon derived hormones.
It is a further objective to find bio-active molecules that are considered nutritionally safe, for example, because they are naturally occurring in specific food resources.
Further objectives of the invention are to prevent or treat diabetes type II, to regulate glucose concentration in serum, to treat or prevent bowel disorders characterized by injury and/or dysfunction of the intestinal mucosal epithelium, to increase the thickness and surface area of the intestinal mucosa, and/or to decrease appetite and food intake.
It is also an objective of the present invention to improve GLP-1 and 2 delivery in humans and mammals.